Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing

Background Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively. Results We systematically investigate both dominance—here representing any non-additive within-locus interaction—and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance. Conclusions Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-023-03060-2.

Aggregate Manhattan plots of the AD GWAS of all physiological traits in pig (g), rat (h) and mouse (i).Associations with -log(P) > 18 are truncated and data points with -log(P) < 2 are not shown.The same coloring scheme is used for the peak QTL of each trait, the solid and dashed horizontal line represents the average suggestive and wholegenome significant thresholds across all traits.Fisher's exact test for the trans-acting enrichment among dominance eQTLs based on the suggestive significant threshold and the whole-genome significant threshold respectively.(n) Dominance trans-acting enrichment (left y-axis, solid lines) and the counts of significant eQTLs (right y-axis, dashed lines) under different -log10(P) eQTL significance thresholds (x-axis).Enrichment is quantified by the -log10(P) values of Fisher exact test between dominance (Add/Dom eQTLs) and regulation types (cis/trans-acting) of significant eQTLs within mouse hippocampus (black), liver (orange) and heart (green), respectively.

Fig. S6.1 Dominant cis and trans transcript eQTLs at the hotspot chr10:85Mb-86Mb
in HS rat heart.(a, e) cis-eQTLs with different inheritance modes, (a) Tbx21 (overdominant) and (e) Nf32l1 (partial-dominant).(b-d) Manhattan plots of overdominant trans-eQTLs for genes Klrb1, Znf683, Cdh17.(f-h) Manhattan plots of partial-dominant trans-eQTLs for genes Gzmb, Cd160, F1lnm2.Within each Manhattan plot, the eQTL is marked by a dotted rectangular frame, with the same colour as the peak SNP dot (Blue -additive; Sky blue -partial-dominant; Purplecomplete-dominant; Red -over-dominant), and all linked SNPs with -log10(P) > 0.5 are coloured the same.The regional Manhattan plots of the peak signal of each eQTL and the scatter plots of two cis-eQTLs are also shown as insets.The pairs of scatter plots to the right of each Manhattan plot compare the expression of each trans-eQTL with Tbx21, Nf32l1, together with their Pearson correlation coefficients and the pvalue of test that the correlation is zero.Each dot represents one animal, colourcoded by the genotype of the peak SNP.Manhattan plots, regional plots and phenotypic distribution boxplots of the peak SNPs from GWAS across eight genes in HS mice hippocampus.Each of these genes is simultaneously trans-regulated by a dominant cis eQTL located in the hotspot (chr1: 161Mb-163Mb), highlighted by red dashed boxes.Fig. S6-5 Dominant eQTLs from a trans-acting hotspot in HS mice lung.Manhattan plots, regional plots and phenotypic distribution boxplots at the peak SNPs across eight genes in HS mice lung, showing seven genes Mef2a (b), Rassf4 (c), Trip12 (d), Dis3 (e), Entpd1 (f), Rbmx (g), Camsap1 (h) that are simultaneously trans-regulated by an overdominant cis eQTL for Nars2 at chr7:103Mb-106Mb (a).Blue and red dashed boxes to highlight the hotspot.plots, regional plots and phenotypic distribution boxplots at the peak SNPs across eight genes in HS mice lung, showing seven genes AL845491.3(b), Abi1 (c), Minpp1 (d), Ttpal (e), Akirin2 (f), Ptpn12 (g), Sardh (h) that are simultaneously trans-regulated by an over-dominant cis eQTL for Itga9 at chr9:117Mb-121Mb (a).Blue and red dashed boxes highlight the hotspot.(l-o) Manhattan plots and regional plots of four colocalized trans-eQTLs in mouse lung, including AC120381.13(OD-eQTL), Klhdc9 (OD-eQTL), Zw10 (CD-eQTL) and Pde4dip (OD-eQTL).All QTLs based on AD model.

Fig. S1. 1
Fig. S1.1 Examples of dominance classifications visualized with different coordinate systems for QTL category comparison.(a) Diagrams illustrating dominance classifications in terms of the phenotypic values associated with each genotype class (AA, AB, BB) and in terms of the additive (a) and dominance (d) deviations from the mid-parent value M(0).(b) and (c) The radiated and longitudinal coordinate systems for QTL display ( (c) is log2 of (b) ).

Fig
Fig. S1.2 Additive (blue bars,    ) and Dominance (red bars,    ) Variance Components of all traits across three populations.(a): F2 pigs, (b): HS rats, (c): HS mice.Each vertical bar represents one trait, labelled on x-axis.Height of each bar represents the total heritability of the corresponding trait, partitioned into additive (blue) and dominance (red) components, as estimated by GCTA.The solid and dashed error bars denote the standard errors of additive and dominance effects in each trait, respectively.Red dashed boxes highlight traits with higher  %&' (

Fig. S2. 1
Fig. S2.1 QTLs detected by AD model.(a-f) show the same data as in Fig 2 where QTLs are classified according to the ratios of their T-statistics from the AD-model, except that in this figure the ratios have not been log-transformed.Each row is one population (a,b: F2 pigs; c,d: HS rats; e,f: HS mice).(a-c): QTLs detected by A-model.(d-f): QTLs detected by AD-model.Within each panel, the x-axis and y-axis represent  )*+ and  ,--, the standardized dominance ( )*+ ) and additive effects ( ,--), respectively.Each dot is one trait, colour-coded by trait type using the same coding as in Fig 2. The dot localizations represent different inheritance models (from deep grey to light grey are additive, partial-dominant, complete-dominant and over-dominant).(g-i)Aggregate Manhattan plots of the AD GWAS of all physiological traits in pig (g), rat (h) and mouse (i).Associations with -log(P) > 18 are truncated and data points with -log(P) < 2 are not shown.The same coloring scheme is used for the peak QTL of each trait, the solid and dashed horizontal line represents the average suggestive and wholegenome significant thresholds across all traits.

Fig. S2. 2
Fig. S2.2Comparison of QTL detection among A, D and AD models.(a-c) Venn diagrams showing overlapping significant SNPs detected by A model (red), D model (blue) and AD model (green) across 247 traits of F2 pigs (a), 207 traits of HS rats (b) and 124 traits of HS mice (c).(d-f) Violin plots showing the distributions of -log(P) values of A model and AD model only using SNPs detected by A model (left), SNPs detected by both A and AD models (middle) and SNPs only detected by D model (right) in pig (d), rat (e) and mouse (f), respectively.(g-i) Similar violin plots comparing SNPs detected by D and AD models in pig (g), rat (h) and mouse (i).(j-l) Similar violin plots comparing SNPs detected by A and D models in pig (j), rat (k) and mouse (l).

Fig
Fig. S3.1 Over-dominant QTLs in F2 pigs.(a-d) Manhattan plots of the Minolta b* value of longissimus dorsi muscle based on (a) A model and (b) AD model.(c) regional plot and (d) genotype boxplot showing phenotypic distribution of the peak SNP of AD model.Within each Manhattan plot, the solid and dashed horizontal line show suggestive and whole-genome significant thresholds and the black dashed box indicates the QTL which was only detected by AD model.Also shown are similarly structured plots for other three traits: (e-h) Minolta c* value of longissimus dorsi muscle, (i-l) the pH value of longissimus dorsi muscle, (m-p) pH value of semimembranosus (m-p).

Fig. S3. 2
Fig. S3.2 Over-dominant HS rat QTLs.(a-d) Manhattan plots of the ratio of T cells to B cells based on A and AD models.Regional Manhattan plots of the peak SNP of AD model showing (b) the LD (r 2 ) with the peak SNP and (c) the different dominance types within the locus.Within each Manhattan plot, the solid and dashed horizontal lines represents suggestive and whole-genome significant thresholds, and the black dashed box highlights the QTL.(d) Boxplot and histogram of phenotypic distributions classified by the peak SNP genotypes.Similar plots shown in (e-h) for absolute T cells counts and (i-l) for proportion of T cells in WBC.

Fig. S3. 3
Fig. S3.3 Over-dominant QTLs implicate a novel causal gene regulating the proportions of CD4+ and CD8+ T cells in HS mice, compared to additive QTL modelling.(a-d) Manhattan plots and regional Manhattan plots of the proportion of CD4+ T cells in CD3+ T cells based on A model (a, b) and AD model (c, d), respectively.(e-h) Manhattan plots and regional Manhattan plots of the proportion of CD8+ T cells in CD3+ T cells based on A model (e, f) and AD model (g, h).Within each Manhattan plot, the blue and red dashed boxes highlight the QTLs detected by Add model and AD model separately, along with the boxplots of phenotypic distribution of the peak SNPs and black arrows are used to indicate the effect directions of peak SNPs.The blue and red dashed ellipses are used to highlight the linked SNP groups for each model in the regional plots, labelled by the closest annotated genes (Bat3: AD Model, Myo1f: A Model).

Fig. S3. 4
Fig. S3.4 Conditional GWAS of the proportion of CD4+ cells in CD3+ cells in HS mice.(a) Initial Manhattan plot after only regressing out regular covariates (gender, experimenter, month).(b) Manhattan plot after regressing out the peak SNP from (a) at chr17: 35,276,617 bp.(c) The Manhattan plot after additionally regressing out the peak SNP in (b) at chr17: 33,744,539 bp.Within each Manhattan plot (a-c), SNPs are colour coded by dominance classification, and insets show Q-Q plots and regional QTL plots around peak SNPs colour coded by R2 LD. (d-f) Three corresponding regional Manhattan plots and phenotype-genotype distributions around the peak SNPs of plots (a-c) in chromosome 17.SNPs coloured based on their dominance types.

Fig. S4. 1
Fig. S4.1 Homologous QTLs for mean corpuscular volume (MCV).(a-d) Manhattan plots in F2 pigs based on (a) AD model and (b) A model (c) regional plot (d) phenotypic distribution boxplot of the peak SNP at chr8: 44,927,836 bp of AD model.(e-h) Homologous QTL for HS rats at the peak SNP chr19: 54,438,416 bp.(i-l) Homologous QTL in HS mice at peak SNP chr1: 157,307,057 bp.Within each Manhattan plot, the solid and dashed horizontal line represents the suggestive and whole-genome significance thresholds and all SNPs with -log10(P) values > 0.5 are coloured according to their dominance classification.

Fig. S4. 2
Fig. S4.2 Homologous QTLs for mean corpuscular volume (MCV).(a-d) Manhattan plots in F2 pigs based on (a) AD model and (b) A model (c) regional plot (d) phenotypic distribution boxplot of the peak SNP at chr8: 44,927,836 bp of AD model.(e-h) Homologous QTL for HS rats at the peak SNP chr19: 54,438,416 bp.(i-l) Homologous QTL in HS mice at peak SNP chr1: 157,307,057 bp.Within each Manhattan plot, the solid and dashed horizontal line represents the suggestive and whole-genome significance thresholds and all SNPs with -log10(P) values > 0.5 are coloured according to their dominance classification.

Fig. S4. 3
Fig. S4.3 Homologous QTLs.(a-b) Ratio of CD4+cells to CD8+ cells in rat and mouse.(c-d) Heart weight of pig and rat.(e-f) Total chloride in rat and mouse.(g-h) High density lipoprotein in rat and mouse.(i-j) Plateletcrit in rat and mouse.(k-l) Platelet count in rat and mouse.(m-n) White blood cell count in pig and rat.(o-p) mean cell hemoglobin concentration on rat and mouse.Within each panel are shown Manhattan plots based on AD model (left) and A model (middle upper) of the specified trait in the population, as well as the regional plot (middle lower) and phenotypic distribution boxplot (right) of the peak SNP in the AD model.

Fig
Fig. S5.1 Trans-acting enrichment among dominant eQTLs in liver and muscle in F2 pigs.(a-h) eQTL locations of transcript level eQTLs, filtered by dominance type.Each dot represents an eQTL significant at suggestive level (i.e. one false positive expected per transcript).x-axis: eQTL chromosome positions (bp), y-axis: physical gene location.First row (a-d): liver; Second row (e-h): muscle.The four columns represent dominance types (blue: additive A, sky blue: partial-dominant PD, purple: complete-dominant CD, red: over-dominant OD).(i) Fisher's exact test for the trans-acting enrichment among dominance eQTLs based on the suggestive significant threshold and the wholegenome significant threshold respectively.(j) Dominance trans-acting enrichment (left y-axis, solid lines) and the counts of significant eQTLs (right y-axis, dashed lines) under different -log10(P) eQTL significance thresholds (x-axis).Enrichment is quantified by the -log10(P) values of Fisher exact test between dominance (Add/Dom eQTLs) and regulation types (cis/trans-acting) of significant eQTLs within rat liver (black) and muscle (orange), respectively.

Fig. S5. 2
Fig. S5.2 Trans-acting enrichment among dominant eQTLs of amygdala and heart tissues in HS rats.(a-h) eQTL locations of gene level eQTLs, filtered by dominance type.Each dot represents an eQTL significant at suggestive level (i.e. one false positive expected per transcript).x-axis: eQTL chromosome positions (bp), y-axis: physical gene location.First row (a-d): amygdala; Second row (e-h): heart.The four columns represent dominance types (blue: additive A, sky blue: partial-dominant PD, purple: complete-dominant CD, red: over-dominant OD).(i) Fisher's exact test for the transacting enrichment among dominance eQTLs based on the suggestive significant threshold and the whole-genome significant threshold respectively.(j) Dominance trans-acting enrichment (left y-axis, solid lines) and the counts of significant eQTLs (right y-axis, dashed lines) under different -log10(P) eQTL significance thresholds (xaxis).Enrichment is quantified by the -log10(P) values of Fisher exact test between dominance (Add/Dom eQTLs) and regulation types (cis/trans-acting) of significant eQTLs within rat amygdala (black) and heart (orange), respectively.

Fig. S5. 3
Fig. S5.3 Trans-acting enrichment among dominant eQTLs of hippocampus, liver and lung tissues in HS mice.(a-h) eQTL locations of transcript level eQTLs, filtered by dominance type.Each dot represents an eQTL significant at suggestive level (i.e. one false positive expected per transcript).x-axis: eQTL chromosome positions (bp), y-axis: physical gene location.First row (a-d): hippocampus; Second row (e-h): liver; Third row (i-l): lung.The four columns represent dominance types (blue: additive A, sky blue: partial-dominant PD, purple: complete-dominant CD, red: over-dominant OD).(m) Fisher's exact test for the trans-acting enrichment among dominance eQTLs based on the suggestive significant threshold and the whole-genome significant threshold respectively.(n) Dominance trans-acting enrichment (left y-axis, solid lines) and the counts of significant eQTLs (right y-axis, dashed lines) under different -log10(P) eQTL significance thresholds (x-axis).Enrichment is quantified by the -log10(P) values of Fisher exact test between dominance (Add/Dom eQTLs) and regulation types (cis/trans-acting) of significant eQTLs within mouse hippocampus (black), liver (orange) and heart (green), respectively.

Fig. S6. 2
Fig. S6.2 Interplay of immunology-related QTLs in HS rats.A locus at chr10: 85Mb-86Mb (cf Fig.5) is an additive QTL for four rat immunology traits, which are also associated with dominant QTLs at chr9: 4Mb-5Mb.Manhattan plots based on AD model for (i) the proportions of CD4+ cells with high expression of CD25 (a-c) (ii) the proportions of CD4+ cells expressing CD25 (d-f) (iii) the proportions of CD8+ cells expressing CD25 (g-i) (iv) the proportions of CD4+CD8-cells (j-l), as well as two corresponding regional Manhattan plots (the left column, the dominant chr9 QTL; the right column, the additive chr10 QTL).Within each Manhattan plot (b, e, h, k), the corresponding GWAS based on A model are shown in the left upper corner.The corresponding phenotype-genotype distribution plots at peak SNPs are also included (peak SNPs located at chromosome 9, m; peak SNPs located at chromosome 10, n).

Fig. S6. 4
Fig. S6.4 Dominant eQTLs from a trans-acting hotspot in HS mice hippocampus.Manhattan plots, regional plots and phenotypic distribution boxplots of the peak SNPs from GWAS across eight genes in HS mice hippocampus.Each of these genes is simultaneously trans-regulated by a dominant cis eQTL located in the hotspot (chr1: 161Mb-163Mb), highlighted by red dashed boxes.

Fig. S6. 7
Fig. S6.7 Tissue-conserved and tissue-specific dominant eQTLs.Examples of tissueconserved eQTLs of GPN1 between liver (a) and muscle (b) in F2 pigs; H2-Q1 between hippocampus (i) and liver (j) in HS mice; 9030612M13Rik between liver (m) and lung (n) in HS mice.Examples of tissue-specific eQTLs shared between Mgea5 of liver (c) and Nudt22 of muscle (d) in F2 pigs; ENSRNOG00000031439 of amygdala (e) and Trappc6a of heart (f) in HS rats; Nut of amygdala (g) and Dyrk3 of heart (h) in HS rats; Dio3 of hippocampus (h) and Pop4 of liver (l) in HS mice; St8sia5 of liver (o) and Clip4 of lung (p) in HS mice.Within each panel are shown the Manhattan plots based on AD model (left) and A model (middle upper) as well as the regional plot (middle lower) and phenotypic distribution boxplot (right) of the peak SNP of AD model.

Fig
Fig. S7.1 Transcript-specific antagonistic dominant eQTLs of RPL14 and LFI44 in HS rat amygdala and heart.(a, c) Plots for RPL14 (a, c) and LFI44 (b, d) of HS rat amygdala (two upper panels) and heart (two lower panels).On the left part of each panel, the top Manhattan plot is based on their overall gene expression level, showing no genome-wide significant eQTLs, the middle and lower Manhattan plots are based on their two transcripts' expression levels, as well as their corresponding regional plots and phenotypic distribution boxplots of the peak SNPs.Within each Manhattan plot, all the SNPs with -log10(P) values > 0.5 are coloured by dominance classification.On the right each panel are shown scatter plots of the correlations of expression levels between each transcript with the corresponding overall gene expression.Within each scatter plot, one dot represents one sample, the dot colors indicate the genotype of the peak SNP.

Fig
Fig. S7.2 Transcript-specific synergistic eQTLs in HS rats.(a-b) Plots of CROT (a) and SLC39A12 (b) of HS rat amygdala.(c-d) Plots of SPPL2A (c) and RT1-M6-2 (d) of HS rat heart.On the left part of each panel, the top Manhattan plot is based on their overall gene expression level, showing no genome-wide significant eQTLs, the middle and lower Manhattan plots are based on their two transcripts' expression levels, as well as their corresponding regional plots and phenotypic distribution boxplots of the peak SNPs.Within each Manhattan plot, all the SNPs with -log10(P) values > 0.5 are coloured by dominance classification.On the right each panel are shown scatter plots of the correlations of expression levels between each transcript with the corresponding overall gene expression.Within each scatter plot, one dot represents one sample, the dot colors indicate the genotype of the peak SNP.

Fig
Fig. S8.1 A pleiotropic over-dominant pig QTL for kidney weight and small intestinal length colocalized with MTCH1 eQTL in F2 pigs.Manhattan plots and regional Manhattan plots (chr7: 37Mb-38Mb) (left, blue/red colors represents the QTL dominance types; right, blue/red colors represents the LD (r 2 ) with the peak SNP) are shown based on AD model GWAS for (1) kidney weight GWAS using array SNPs (a-c),(2) small intestinal length using array SNPs (d-f), as well as the MTCH1 expression level in F2 pigs liver (g-i) and muscle (j-l), respectively.The gene structure plot (g, right upper) from UCSC Genome Browser illustrating MTCH1 as the nearest gene to the finemapped QTL regions of two physical traits (a, d) based on array SNPs.